The breathless complications of anti-MDA-5-positive dermatomyositis

By Warren R. Heymann, MD, FAAD
Oct. 30, 2024
Vol. 6, No. 44

Dermatologists are familiar with the spectrum of dermatomyositis (DM) — classic DM, juvenile DM, amyopathic DM, and cancer-associated DM. Clinically, amyopathic DM is a form in which the patients typically develop characteristic cutaneous features of DM [heliotrope rash, Gottron’s papules, periungual erythema, mechanic’s hands, palmar papules, shawl sign, holster sign]. A subtype of amyopathic DM is anti-MDA5 DM (anti-melanoma differentiation-associated-5-positive DM), additionally characterized by cutaneous ulcerations and rapidly progressive interstitial lung disease (RP-ILD). The prevalence of the anti-MDA5 DM is higher in Japanese and Chinese cohorts (15–36.6%) than the prevalence in the European population (1.3 to 10%). (1) This commentary will focus on the potentially life-threatening complication of pneumomediastinum (PM) in patients afflicted with anti-MDA5-positive DM.

The initial report of PM in DM was a 42-year-old man with DM and skin ulcers. (2) I suspect this patient had anti-MDA5-positive DM but this case was published 19 years before Sato et al. recognized autoantibodies to a 140-kd polypeptide in 8 of 42 DM patients. All 8 had clinically amyopathic DM — hence the name anti-CADM-140. Seven of these 8 patients had interstitial lung disease (ILD), which was rapidly progressive (RP-ILD) in 4 cases. (3) Subsequently, it was discovered that the target antigen of these antibodies was a protein implicated in the innate immune response against viruses that is encoded by the melanoma differentiation-associated gene 5. (1)

According to Subki et al, “Pneumomediastinum is a condition where air extravasates from within the airways and migrates into the mediastinal space. It commonly results from traumatic injury, acute mediastinitis, or assisted ventilation. Spontaneous pneumomediastinum may occur due to air leakage through non-partitional alveolar walls and subsequent medial dissection along pulmonary vessels to the mediastinum. When the peripherally dissecting air gets trapped as subpleural blebs, or if there are visceral pleura ruptures, air can escape into the pleural space, resulting in pneumothorax.” (4)

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Huang et al investigated the clinical characteristics of subcutaneous emphysema (SE) and mediastinal emphysema (ME) occurring in patients with anti-MDA5-positive DM-ILD by performing a retrospective study of 117 anti-MDA5-positive DM-ILD patients. All patients underwent an assessment of autoantibodies, serum ferritin levels, and pulmonary high-resolution CT scans. In patients with anti-MDA5-positive DM-ILD, the incidence of SE/ME was found to be 11.1%, which was significantly higher compared to patients with anti-synthetase syndrome (p<0.01). The mortality rate among anti-MDA5-positive DM-ILD patients with SE/ME was significantly higher than those without SE/ME (p=0.0022). There was no statistically significant difference in the occurrence of SE/ME between patients with positive anti-Ro-52 antibodies and those with negative anti-Ro-52 antibodies (p=0.18). Patients with higher serum ferritin levels had a higher likelihood of developing SE/ME compared to patients with lower serum ferritin levels (p<0.01). Among 13 anti-MDA5-positive DM-ILD patients with SE/ME, 6 (46.2%) developed SE/ME within 1 month of being diagnosed and 53.8% of patients underwent positive pressure ventilation prior to the onset of SE/ME. The authors concluded that SE/ME is not uncommon in anti-MDA5-positive DM-ILD and is an important factor associated with poor patient prognosis. The occurrence of SE/ME correlates with high levels of serum ferritin and is not related to anti-Ro-52 antibodies. Close attention should be paid to SE/ME caused by positive pressure ventilation in anti-MDA5-positive DM-ILD patients. (5) Other authors suggest that patients with positive anti-MDA5 and anti-Ro52 antibodies (especially those with high titers) have a higher risk of RP-ILD and a lower survival rate compared to patients with only anti-MDA5 antibodies. (6)

Although the pathophysiology of PM associated with anti-MDA5 is not explicit, the following factors are likely contributory: a) ILD distorts lung architecture causing fragility of alveoli; b) vasculopathy; and c) glucocorticoids used in therapy may weaken the pulmonary interstitium. (7) Additionally, a retrospective study of 385 anti-MDA5-positive DM patients complicated by spontaneous PM showed a significantly higher frequency of fever, dyspnea, and pulmonary infection including viral (cytomegalovirus) and fungal infections (Pneumocystis jirovecii) compared to those without SPM (P all < 0.05) that are considered risk factors for PM. (8)

Currently there is no standard therapeutic regimen for PM in MDA5-positive DM patients — the dermatologist’s role is to think about the possibilities of RP-ILD and PM in dyspneic patients and refer the patient accordingly. Although high-resolution CT of the chest is the preferred imaging modality because of its high sensitivity for detecting ILD, pulmonary function studies with DLCO (diffusion capacity of the lung for carbon monoxide) might be a prudent initial screening test to limit cumulative radiation exposure (with a low threshold to perform a high-resolution CT if any abnormalities are discovered). (9) Multidisciplinary therapy with the combination of high-dose glucocorticoids, aggressive immunosuppressants (cyclophosphamide or tacrolimus), tofacitinib and rituximab, with or without surgery or oxygen support, is used as a pattern for the patients. (7) More studies are needed to determine the intensity of immunosuppression and mechanical oxygen support because of the potential for exacerbation of pulmonary complications.

Point to Remember: Rapidly progressing interstitial lung disease and pneumomediastinum are potentially life-threatening complications of anti-MDA5-postiive dermatomyositis. Dyspneic patients with this disease mandate urgent assessment.

Our expert’s viewpoint

Katharina S. Shaw, MD
Instructor of Dermatology, Perelman School of Medicine at the University of Pennsylvania
Co-Director of the Rheumatology-Dermatology Clinic, Children’s Hospital of Philadelphia

I distinctly remember my first encounter with an MDA-5 dermatomyositis (DM) patient. It was my first week of rheumatology-dermatology fellowship, and a woman in her 40s came in with a complaint of “rash.” At first glance, her exam seemed unremarkable. She had no facial or eyelid erythema. She had some subtle hair thinning and an isolated, scaly patch on her extensor elbow that could be mistaken for psoriasis. Her oral exam revealed a few subtle erosions on her buccal mucosa. Her clinical findings became more interesting when I studied her hands — she had erythematous papules (Gottron’s papules) with incipient areas of ulceration overlying her knuckles and extensor finger joints. When she flipped her hands over … BAM! Multiple, tender erythematous macules and papules, some ulcerated and on a livedoid background that hugged her finger creases. My fellowship director, the brilliant Dr. Ruth Ann Vleugels, took one look at these so-called “MDA-5 palms” and made an immediate diagnosis of MDA-5 DM. Despite the patient not complaining of any dyspnea, PFTs obtained that day revealed a restrictive defect. A high-resolution chest CT later that week demonstrated early findings of ILD. Notably, she was referred to pulmonology and started on disease-modifying therapy with mycophenolate mofetil before her myositis specific autoantibody (MSA) panel ever resulted (which it did, 3 months later, positive for MDA-5 autoantibodies).

This brings me to perhaps my most important “pearl” when it comes to DM and MDA-5 DM, in particular. Dr. Heymann has beautifully laid out the importance of being aware of the very serious pulmonary complications of MDA-5 DM. But I must pause here and urge readers to be comfortable recognizing the mucocutaneous features of MDA-5 DM (and making the diagnosis) in the absence of confirmatory MSA testing. At present, there is still no gold-standard for MSA testing. Not only are there several different methodologies for detecting MSAs in practice (ranging from immunoprecipitation to ELISA to line immunoblot assays), but due to individual laboratories utilizing their own proprietary assays, MSA results can vary, even within the same patient. Moreover, turnaround times can exceed weeks to months. As Dr. Heymann points out, delaying systemic work-up for MSA testing can have significant systemic consequences. Thus, familiarity with the unique mucocutaneous phenotype of MDA-5 DM — which includes painful palmar papules, oral ulcers, nonscarring alopecia, cutaneous ulceration, lateral digit hyperkeratosis and occasionally, panniculitis — remains paramount. With a careful skin exam, dermatologists can recognize MDA-5 DM early, thereby facilitating potentially life-saving screening and management of its systemic complications.

1. Bobirca A, Alexandru C, Musetescu AE, Bobirca F, Florescu AT, Constantin M, Tebeica T, Florescu A, Isac S, Bojinca M, Ancuta I. Anti-MDA5 Amyopathic Dermatomyositis-A Diagnostic and Therapeutic Challenge. Life (Basel). 2022 Jul 23;12(8):1108. doi: 10.3390/life12081108. PMID: 35892910; PMCID: PMC9329888.

2. Bradley JD. Spontaneous pneumomediastinum in adult dermatomyositis. Ann Rheum Dis. 1986 Sep;45(9):780-2. doi: 10.1136/ard.45.9.780. PMID: 3767467; PMCID: PMC1001988.

3. Sato S, Hirakata M, Kuwana M, Suwa A, Inada S, Mimori T, Nishikawa T, Oddis CV, Ikeda Y. Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum. 2005 May;52(5):1571-6. doi: 10.1002/art.21023. PMID: 15880816.

4. Subki AH, Almani IM, Albeity A, Aljabri BK, Alsolaimani R, Halabi H. Spontaneous Pneumomediastinum and Subcutaneous Emphysema in Dermatomyositis: A Case Series and Literature Review. J Inflamm Res. 2023 Apr 3;16:1431-1441. doi: 10.2147/JIR.S389839. PMID: 37034473; PMCID: PMC10081667.

5. Huang W, Chen D, Ren F, Luo L, Zhou J, Huang D, Tian M, Qian K, Jiang Y, Tang L. The clinical characteristics of subcutaneous and mediastinal emphysema in anti-melanoma differentiation-associated 5 positive dermatomyositis associated with interstitial lung disease. Clin Exp Rheumatol. 2024 Feb;42(2):262-268. doi: 10.55563/clinexprheumatol/84kd56. Epub 2023 Dec 22. PMID: 38147317.

6. Figueiredo, C., Matos, A. L, Calvao, J., & Goncalo, M. (2024). Three cases of Anti-MDA5 positive dermatomyositis with interstitial lung disease and pneumomediastium. Dermatology Online Journal, 30(1). http://dx.doi.org/10.5070/D330163301

7. Yang J, Yan B. Rare complications of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis: Time to nip them in the bud. Front Immunol. 2022 Oct 6;13:1009546. doi: 10.3389/fimmu.2022.1009546. PMID: 36275649; PMCID: PMC9584642.

8. Jin Q, Lin S, Chen X, Xu Y, Tian X, He L, Jiang W, Chen F, Shu X, Lu X, Peng Q, Wang G. Spontaneous pneumomediastinum in anti-MDA5-positive dermatomyositis: Prevalence, risk factors, and prognosis. Semin Arthritis Rheum. 2024 Apr;65:152352. doi: 10.1016/j.semarthrit.2023.152352. Epub 2024 Jan 3. PMID: 38185078.

9. Kurtzman DJB, Vleugels RA. Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: A concise review with an emphasis on distinctive clinical features. J Am Acad Dermatol. 2018 Apr;78(4):776-785. doi: 10.1016/j.jaad.2017.12.010. Epub 2017 Dec 9. PMID: 29229575.

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